This invention relates to the decolorization, separation, and purification of water-soluble, nonionic compounds from solutions containing nonionic compound impurities and, more particularly, the decolorization, separation, and purification of water-soluble, nonionic contrast media compounds from nonionic compound impurities by large, factory scale reversed phase chromatography.
In the preparation of nonionic compounds, such as nonionic X-ray contrast media and magnetic resonance imaging (MRI) agents, nonionic impurities are produced which are difficult to remove in an efficient and economical manner. Nonionic, low osmolar X-ray contrast media and MRI agents have become generally regarded as being safe and providing advantageous contrast enhancement in various radiographic procedures. However, such nonionic X-ray contrast media are more costly than ionic X-ray contrast media because of the complexity of the processes required for their synthesis and also because in many instances, the nonionic, non-polar impurities associated therewith require multiple crystallization and/or precipitation procedures for satisfactory removal. Thus, in the preparation of the nonionic contrast agents iohexol (N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6- triiodoisophthalamide), the crude iohexol is subjected to several crystallization and precipitation procedures in order to remove the lipophilic nonionic impurities (Oslo Symposium, Ion Exchange Solvent Extraction, Paper 49IYAP 1982). Similarly, in Haavaldsen et al. X-Ray Contrast Agents, Acta Pharm. Succ. 20, 219-232 (1983), the preparation of iohexol and other nonionic derivatives of 5-amino-2,4,6-triiodoisophthalamide is described as involving multiple crystallization steps and normal phase preparative liquid chromatography for purification of the desired end products. Such crystallization purification procedures are also described in U.S. Pat. No. 4,250,113, dated Feb. 10, 1981, directed to iohexol and related nonionic compounds and in U.S. Pat. No. 4,001,323, dated Jan. 4, 1977, directed to the nonionic X-ray contrast agent iopamidol (N, N'-bis(1,3-dihydroxypropyl -5-lactylamido-2,4,6-triiodoisophthalamide).
Skjold and Berg (Journal of Chromatography, 366 (1986) 299-309) describe the use of laboratory scale reversed-phase preparative liquid chromatography for the removal of ionic impurities from solutions containing such impurities and water-soluble, nonionic X-ray contrast agents. In the chromatographic process described, the loading ratio of chromatographic packing material to crude product to be purified is on the order of 31.6:1 to 19.6:1 and the mobile phases used for eluting the chromatographic column are mixtures of methanol and water alone or with the addition of ammonium acetate buffers, tetrabutylammonium chloride and phosphate buffer.
Schering AG German patent application P31 10 737 A1, published Oct. 14, 1982, discloses a chromatographic process for the separation and purification of water-soluble, nonionic compounds from solutions containing ionic compounds which employs a silanized separating material, such as silanized silica gel, as the chromatographic packing material and water or water-alcohol mixtures as the eluting solvent. The process is described as being applicable to the separation and purification of water-soluble, nonionic X-ray contrast media from water-soluble inorganic or organic salts.
There remains a need for an efficient and effective factory scale chromatographic process for the decolorization, separation, and purification of water-soluble, nonionic contrast media compounds and MRI agents from solutions containing nonionic compound impurities.